Arginine-truncation and mast cell degranulation SAR study.
| Compound | Sequencea | KRASG12D GDP TR-FRET EC50 (nM) | AsPC-1 pERK EC50 1 h/18 h (μM) | # of Arg | rMCD histamine release threshold (μM) | NanoClick EC50 4 h/18 h (nM) |
|---|---|---|---|---|---|---|
| MP-4090 | Ac-K(N3)-rrrr-cyclo(c(methylene)PLYISYDPVC)-rrrr-NH2 | 140.7 | 3.6/30.8 | 8 | ≥0.14 | 251/35 |
| MP-6483 | Ac-K(N3)-RRRR-cyclo(c(methylene)PLYISYDPVC)-RRRR-NH2 | 172.4 | 15.9/>50 | 8 | ≥0.14 | 2693/636 |
| 23 | Ac-K(N3)-RRR-cyclo(c(methylene)PLYISYDPVC)-RRR-NH2 | 75.8 | >50/>50 | 6 | ≥0.14 | 3314/>10 000 |
| MP-1687 | Ac-K(N3)-RR-cyclo(c(methylene)PLYISYDPVC)- RR-NH2 | 59.4 | >50/>50 | 4 | ≥3.7 | 4552/4711 |
| MP-9903 | Ac-K(N3)-R-cyclo(c(methylene)PLYISYDPVC)-R-NH2 | 138.6 | >50/>50 | 2 | >100 | 6939/6828 |
| 24 | Ac-K(N3)-cyclo(c(methylene)PLYISYDPVC)-R-NH2 | 187.6 | >50/>50 | 1 | >100 | >10 000/4462 |
| 25 | Ac-K(N3)-cyclo(c(methylene)PLYISYDPVC)-NH2 | 409.5 | >50/>50 | 0 | >100 | >10 000/5136 |
a
Lower case letters represent d-amino acids.